DISCUSSION
To our knowledge, this is the first meta-analysis of trials exclusively carried out in
children and adolescent populations that explored the efficacy of adding ICS to SC compared with SC alone for acute asthma when consulting in the ED or during hospitalization. Our study demonstrates that in children hospitalized with an acute asthma episode adding budesonide significantly reduces the LOS by more than one day. Among the trials done in the ED, adding budesonide significantly improved the acute asthma severity score, especially when using high doses of budesonide (≥2 mg).
Objective measurements such as SpO2 and respiratory and heart rates were significantly different between children treated with the addition of budesonide versus controls. The SpO2improved, while respiratory and heart rates decreased in the budesonide group only among trials with hospitalized children; however, not pooled data analysis was able to performed. It is important to mention that heart rate could be influenced by the SABA drugs included in the protocol. In terms of lung function, only two studies (one in the ED and one in hospitalized children) reported this outcome, and in both children on ICS+SC significantly improved the PEFR in comparison with SC. The same result was before described in adults using PEFR, but not with FEV18. Similarly, the present review shows that adding budesonide to SC does not result in more AEs or SAEs, as was described in the last Cochrane review8.
The most recent GINA guidelines4 stated that a high dose of ICS within the first hours after presentation to ED reduces the need for hospitalization in patients who did not receive SC, but the addition of ICS to SC is inconclusive, and the type of ICS, doses, and duration remain unclear; moreover, the cost is an issue that remains to be resolved. Likewise, the latest Cochrane review8 of five studies (n=433 patients), but only two studies20,23 in children, showed that ICS plus SC significantly reduces hospital admission compared with SC, but with high heterogenicity (OR=0.54 [0.36 to 0.81], I2=52%), and stated the necessity for further research “to clarify the most appropriate drug dosage and delivery device, and to define which patients are most likely to benefit from ICS therapy”. Our systematic review of nine studies done exclusively in a population of children with acute asthma (n=1473) showed that adding budesonide via nebulizer did not reduce hospital admission, but significantly reduces the LOS, and improves the asthma severity score in the ED, especially when using high doses of budesonide. In terms of cost, in a recent cost-effectiveness analysis done in a middle-high income country, we demonstrated that ICS in addition to SCs compared with standard therapy with SCs for treating pediatric asthma model showed that compared to SCs, therapy with ICS+SCs was associated with lower total costs (US$ 88.8 vs.US$97.7 average cost per patient) and a lower probability of hospital admission (0.9060 vs. 0.9000)29.
The biological explanation of the superiority of adding ICS to SC vs. SC is the addition of the non-genomic effect, which only ICS exhibit (i.e. activation of endothelial NO synthase and NO synthesis, increasing the noradrenergic neurotransmission in the airway vasculature and therefore reducing the airway blood flow10, a desirable effect in asthmatic patients, where a significant increased blood flow in the airway mucosa ocurrs11), to the genomic effect of SC. Another advantage of adding ICS is their very rapid onset of action (in minutes) in contrast to the slow onset of action of SCs (3–4 h after administration). An additional mechanism is that ICS administration simultaneously with SABA could acutely potentiate its bronchodilation effect30.
In all the RCTs included in this systematic review, the ICS used was budesonide. A study in vivo31 showed that budesonide oleate is formed rapidly in human airways after inhalation and is detectable in lung tissue for almost 2 days after a single inhalation. Esterification takes place intracellularly within the lungs, and the sustained action of budesonide is explained by this fatty acid conjugation. This sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and its suitability for once-daily administration31. Budesonide, compared with other ICS, had the highest vasoconstrictive effect in airway blood flow32,33, and since airway blood flow is increased in asthmatics, the vasoconstrictive effect of ICS is beneficial. Also, when budesonide was nebulized up to 26% of the drug is systemically bioavailable in children34.
This study has several limitations. First, no studies using ICS delivery by MDI were found, and therefore the results of budesonide via nebulizer cannot be extrapolated to ICS delivery via MDI or to other types of ICS. Also, it was not possible to evaluate the relative efficacy of the different nebulizer devices used in these trials. Second, only two studies measured lung function. Third, differences in type of SC was not analysis in detail. Fourth, the minimal clinically important difference for each asthma score using in the trials was not reported. Five, since better results were obtained using 2mg doses of budesonide, more trials with higher doses need to be performed. The strength of this study is that it includes nine RCTs exclusively carried out in a population of children, most of them with high-quality methodology, from seven different countries around the world involving more than 1400 patients with asthma.
In conclusion, adding budesonide to SC, compared with SC alone, for acute asthma in hospitalized children significantly reduces the LOS by more than one day, and significantly improves the acute asthma severity score for patients in the ED (especially using ≥2 mg).
List of Abbreviations: AEs= adverse effects, API= asthma predictive index, ED= emergency department, ICS= inhaled corticosteroids, LOS= length of stay, MDI= metered dose inhaler, NO= nitric oxide, PEFR= peak expiratory flow rate, RCTs= randomized clinical trials, RR= risk ratios, SAEs= severe adverse effects, SABA= beta-2 agonists, SpO2= oxygen saturation, SC= systemic corticosteroids, SMD= standardized mean differences.